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Parallel quantification of large numbers of messenger RNA transcripts using microarray technology promises to provide detailed insight into cellular processes involved in the regulation of gene expression. This should allow new understanding of signalling networks that operate in the cell and of the molecular basis and classification of disease. But can the technology deliver such far-reaching promises?
Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.
BACKGROUND: Glial tumors are the most common tumors of the central nervous system, affecting individuals of all ages. Conventional cytogenetics have been unable to identify a consistent chromosomal translocation or rearrangement in this group of tumors; thus, more advanced molecular cytogenetic approaches are required. METHODS AND RESULTS: In this study, 16 glial tumors, including two recurrences and six glioma cell lines, were analyzed by spectral karyotyping (SKY) and comparative genomic hybridization (CGH). From 169 rearrangements detected by SKY, chromosomes 1 and 10 were the most frequently affected by translocation (18 of 169 and 16 of 169 rearrangements, respectively). Other frequently altered chromosomes included chromosomes 3 (13 of 169 rearrangements), 5 (ten of 169 rearrangements), 7 (ten of 169 rearrangements ), and 11 (ten of 169 rearrangements). A clustering of centromeric breakpoints was detected in chromosomes 3, 5, 10, 11, 16, 17, and 20. CGH analysis identified consistent gain of part or all of chromosome 7 among the 10 astrocytic tumors (five of ten specimens) in the study group. Analysis of the three gangliogliomas and one ependymoma identified a much simpler pattern of primarily numerical change. CONCLUSION: Application of improved cytogenetic methods can increase our abilities to progress toward effective strategies of molecular diagnosis and classification of glial tumors.
Proteases that are encoded by animal picornaviruses and plant como- and potyviruses form a related group of cysteine-active-center enzymes that are essential for virus maturation. We show that these proteins are homologous to the family of trypsin-like serine proteases. In our model, the active-site nucleophile of the trypsin catalytic triad, Ser-195, is changed to a Cys residue in these viral proteases. The other two residues of the triad, His-57 and Asp-102, are otherwise absolutely conserved in all the viral protease sequences. Secondary structure analysis of aligned sequences suggests the location of the component strands of the twin beta-barrel trypsin fold in the viral proteases. Unexpectedly, the 2a and 3c subclasses of viral cysteine proteases are, respectively, homologous to the small and large structural subclasses of trypsin-like serine proteases. This classification allows the molecular mapping of residues from viral sequences onto related tertiary structures; we precisely identify amino acids that are strong determinants of specificity for both small and large viral cysteine proteases.
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BRENDA (BRaunschweig ENzyme DAtabase) represents a comprehensive collection of enzyme and metabolic information, based on primary literature. The database contains data from at least 83,000 different enzymes from 9800 different organisms, classified in approximately 4200 EC numbers. BRENDA includes biochemical and molecular information on classification and nomenclature, reaction and specificity, functional parameters, occurrence, enzyme structure, application, engineering, stability, disease, isolation and preparation, links and literature references. The data are extracted and evaluated from approximately 46,000 references, which are linked to PubMed as long as the reference is cited in PubMed. In the past year BRENDA has undergone major changes including a large increase in updating speed with >50% of all data updated in 2002 or in the first half of 2003, the development of a new EC-tree browser, a taxonomy-tree browser, a chemical substructure search engine for ligand structure, the development of controlled vocabulary, an ontology for some information fields and a thesaurus for ligand names. The database is accessible free of charge to the academic community at http://www.brenda. uni-koeln.de.
IMPORTANCE: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE), are rare but life-threatening drug hypersensitivity syndromes. Due to their low incidence and diagnostic complexity, large-scale characterization of SCAR is challenging. OBJECTIVE: To characterize the demographics, causative agents, trends, latency, and phenotypic overlap of SCAR using a large-scale, sanitized pharmacovigilance dataset from FAERS (FDA Adverse Event Reporting System). DESIGN: Cross-sectional study of spontaneous adverse event reports. Cases were drawn from the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) from January 2004 to December 2023 and subjected to sanitization and deduplication. Disproportionality analysis was used to characterize causative agents. Machine learning (random forest classifiers) was used to analyze predictors of drug latency and mortality. SETTING: Global pharmacovigilance reports submitted to FAERS. PARTICIPANTS: A total of 56,683 deduplicated SCAR reports were identified, representing 0.33% of reports during the study period. EXPOSURES: Suspected causative drugs, including both small molecules and biologics. MAIN OUTCOMES AND MEASURES: Main outcomes included the frequency and distribution of SCAR syndromes, reporting trends over time, latency from drug start to reaction onset, drug-specific disproportionality (PRR, ROR, IC), and co-reporting between SCAR types and related conditions. RESULTS: A total of 56,683 unique SCAR reports were identified, including SJS-TEN (28,871), DRESS (22,444), AGEP (6,183), and GBFDE (150). We identified 237 drugs with significant disproportionality for SCAR overall. Co-reporting between SCARs was significantly enriched (p < 1e-200), suggesting overlapping phenotypes. Latency varied by drug and syndrome (median: GBFDE 3 days, AGEP 4 days, SJS-TEN 12 days, DRESS 20 days). CONCLUSIONS AND RELEVANCE: SCAR syndromes display distinct but overlapping phenotypes, with variable latency and diverse causative agents. These findings, based on the largest SCAR dataset to date, highlight the need for improved classification frameworks and molecular validation. Large-scale pharmacovigilance, integrated with genomic and histopathologic data, will be critical to improving diagnosis, mechanistic understanding, and clinical management of SCAR.
We undertook a comprehensive phylogenetic study to establish the genetic relationship among the viruses of the genus Flavivirus and to compare the classification based on molecular phylogeny with the existing serologic method. By using a combination of quantitative definitions (bootstrap support level and the pairwise nucleotide sequence identity), the viruses could be classified into clusters, clades, and species. Our phylogenetic study revealed for the first time that from the putative ancestor two branches, non-vector and vector-borne virus clusters, evolved and from the latter cluster emerged tick-borne and mosquito-borne virus clusters. Provided that the theory of arthropod association being an acquired trait was correct, pairwise nucleotide sequence identity among these three clusters provided supporting data for a possibility that the non-vector cluster evolved first, followed by the separation of tick-borne and mosquito-borne virus clusters in that order. Clades established in our study correlated significantly with existing antigenic complexes. We also resolved many of the past taxonomic problems by establishing phylogenetic relationships of the antigenically unclassified viruses with the well-established viruses and by identifying synonymous viruses.
Epidermolysis bullosa is a group of genetically determined diseases characterized by abnormal fragility of the skin and mucosa. In this chapter, we review current thinking about classification, pathogenesis, and molecular genetics, and we discuss management guidelines.
Primary gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is a distinct entity with its own histological classification. Epidemiological, histomorphological, molecular biological and experimental data clearly underline that infection of the gastric mucosa by Helicobacter pylori plays an important role in both the development and progression of MALT lymphoma. Considering the histological grade of malignancy and dissemination (stage) of the disease as decisive prognostic factors, and therapeutic determinants, endoscopic bioptical diagnosis and endoscopic ultrasound are of particular importance. In cases of localized (stage 1), low grade lymphoma, eradication of H pylori offers a promising and fascinating therapeutic option. Surgical resection, radiotherapy or chemotherapy, and their combination, have proven to be effective treatment modalities. There is a need to clarify whether operative or conservative therapeutic strategies should be favoured in the future.
Anaplastic oligodendroglial tumours (oligodendrogliomas and oligoastro-cytomas) have a definite better prognosis than diffuse astrocytic gliomas (glioblastomas and anaplastic astrocytomas). Surgery relieves neurological symptoms and provides tissue for classification, grading and molecular characterisation of the tumour. Historically, radiation therapy has been the sole postoperative treatment for patients with anaplastic oligodendroglial tumours, but this policy has been challenged in the last few years by the discovery that these tumours are chemosensitive. Procarbazine, lomustine and vincristine (PCV) and temozolomide are the most active drugs, but it is still unclear which is the best first-line regimen. The most appropriate timing for chemotherapy (neoadjuvant, adjuvant, at recurrence) is unknown and is currently being explored in prospective studies. The goals of neoadjuvant chemotherapy (PCV, temozolomide, high-dose alkylating agents with stem cell rescue) are to defer radiotherapy or to reduce the radiation fields for a conformal treatment in responding patients. Molecular genetic analysis is increasingly employed for both diagnostic and prognostic purposes. Loss of heterozygosity on 1p and 19q is the key alteration for predicting the prognosis and the response to chemotherapy.
Evaluation of: Gonzalgo ML, Yegnasubramanian S, Yan G et al.: Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis. Clin. Cancer Res. 10 (21), 7276-7283 (2004). This study identified RASSF1A promoter methylation as a valuable epigenetic marker for renal cancer, eventually indicating more aggressive disease. Overall, 16 gene promoters were surveyed for hypermethylation in a series of 38 renal cell tumors (comprising papillary and clear-cell renal cell carcinoma, and oncocytoma) and paired normal tissue samples. Among the target genes analyzed, RASSF1A emerged as the most frequently methylated in renal tumors and also at higher levels. Statistical analyses showed a significant association between RASSF1A promoter methylation and higher pathological stage, but not with tumor size or nuclear grade. The discriminative power of a quantitative approach allowed for a segregation between renal carcinomas and oncocytomas, using a self-organizing hierarchical neural network. These results hold the promise that epigenetic-based markers might prove clinically useful for the management of patients with renal tumors. Nevertheless, further studies, including larger sets of patients and more diversified renal tumors, as well as benign lesions, are needed to validate these preliminary results.
We summarize the clinical data of 47 patients with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. The pedigrees of 14 German families were studied. In three families there was only one member affected, two or more affected members were found in the other families. These family pedigrees were consistent with autosomal dominant inheritance. Variable expression of the disease was noted in members within one family. Over pressure points punctate keratoses coalesced into hyperkeratotic plaques. There was palmoplantar hyperhidrosis in 3 families associated with keratosis. Continuous systemic retinoid treatment can clear symptoms. Future genetic classification on a molecular basis may reveal the existence of more than one entity of this clinically heterogeneous genodermatosis.
An unusual posterior fossa neoplasm in a 26-year-old woman with short history of the cerebellar symptoms is presented. CT and MR images showed the tumor within the cerebellopontine angle, suspected as meningioma. At surgery, the tumor was dura-attached and did not infiltrate the arachnoid. Histologically, the neoplasm was a small blue cell tumor with solid and microcystic pattern, consistent with primitive neuroectodermal tumor (PNET). Immunohistochemically the cells were strongly positive for NCAM and GFAP. Fluorescence in situ hybridization (FISH) was performed with the cosmids G9 and F7 (flanking EWSR1/22q12 region) DNA probes and dual-color spectrum-orange LSI HER-2/neu (17q11.2)/spectrum green CEP17 (17p11.1-q11.1) DNA probe. The presence of isochromosome 17q within neoplastic cells was found. The tumor was classified as a medulloblastoma. We demonstrate the utility of a multidisciplinary approach to nervous system tumor diagnosis. The clinical features together with histological, immunohistochemical, and characteristic molecular alteration allowed classification of the presented case.
Genetic diversity analysis of diploid and allotetraploid cotton species was carried out using SSR molecular markers by selecting representative species having A and (or) D genome in Gossypium. Ten diploid cotton species in A and D genomes had high polymorphism and the molecular cluster was consistent with Gossypium classification previously reported by Fryxell. From molecular level, G. gossypioides belonging to D genome had low similarity matrix compared with other diploid D genome species. Diploid cotton species separately having A or D genome had their high similarity matrix. The research supported that G. gossypioides was the most original cotton species among all D genome species, different genomes in Gossypium had common origin and made evolution separately. To better understand genetic events that accompany allopolyploid formation, we add 2 cultivated allotetraploid cotton species in our research materials. However, the results showed that it was not appropriate to study evolution of A and D genome in Gossypium using cultivated allotetraploid cotton species. In order to solve the question, original arboreum, herbaceum and wild types of allotetraploid cotton species should be adopted. Further evolution research on cotton species based on the transcription level of cotton genome is being carried on.
Recent progress in molecular biology, cytogenetics, classification and grading of soft tissue sarcomas is briefly reviewed. It is emphasized that peer review of histopathology is highly desirable. Finally, equipped with modern imaging techniques, the radiologist can anticipate an increasing role in the aspiration cytology of deep seated soft tissue tumors.
Streptococcus agalactiae is an endogenous bacterium that has emerged in the last 20 years as an etiological agent in both neonatal and perinatal infections, and in immunocompromised patients. The differentiation of the capsular polysaccharide, the presence of surface proteins c, X, R, and molecular methods allow classification in serotypes and genotypes. This identification is a useful tool for epidemiological purposes and virulence studies in this bacterium. The objective of this work was to study the serotypes and the antimicrobial susceptibility of isolates recovered from invasive diseases in different areas of Argentina. In the analyzed sample a fair predominance of Ia and III serotypes was recovered, followed by II and IV serotypes. All the isolates were found to be sensitive to penicillin. A 6% of resistance to erythromycin and a 4.5% to clindamycin were detected. In three of the isolates, constitutive MLS phenotype (resistance to macrolides, lincosamins and streptogramins) was founded, while in the remaining one, inducible MLS phenotype was detected. These results stress the importance of conducting a surveillance of the prevalent serotypes in our country with the goal of future prevention of this disease with an effective vaccine. The knowledge of the antimicrobial susceptibility profile will be also important to obtain therapeutic success in the treatment.
The introduction of antibodies specific for distinct basement membrane zone components is helpful in the diagnosis of hereditary mechanobullous diseases. In addition, these reagents have implications for investigation of the pathogenesis of these disorders, which might help to establish the classification based on molecular defects. Antibodies by means of indirect immune fluorescent microscopy can play a key role in the differential diagnosis of junctional and dystrophic types of epidermolysis bullosa. In epidermolysis bullosa hereditaria dystrophica, a disturbance in the regulation of collagenase activity has already been well documented, and several therapeutic approaches have been carried out based on the inhibition of collagenase activity. Concomitant inhibition of collagenolytic activity and stabilization of collagen fibrils might furthermore be helpful in the treatment of these patients. There are already several reports on the therapeutic effects of collagenase inhibitors, and stabilization of collagen fibrils in vitro has been demonstrated by (+)-cyanidanol-3. The preliminary results on therapeutic application of this drug seem to be promising.